Pathway Map Details

Immune response_IFN alpha/beta signaling pathway

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Object list (links open in MetaCore):

STAT1/STAT2, PML, JAK1, IRF2, ISG15, IRF1, ISGF3, ISG54, SHP-1, USP18, IFN-alpha/beta receptor, IFNAR2, STAT2, IFN-beta, IFI6, PTP-1B, IFN-alpha, IRF9, PRMT1, STAT1, IFNAR1, SHP-2, SOCS1, Tyk2


IFN alpha/beta signaling pathway

Interferons (IFNs) are pleiotropic cytokines that exhibit important biologic activities, including antiviral, antiproliferative, antitumor and immunomodulatory effects [1], [2].

IFNs are classified as either Type I or Type II. Type I IFNs include the IFN-alpha family of 13 subtypes, IFN-beta, IFN-omega, IFN-tau, IFN-kappa, IFN-lambda, and IFN-zeta. By contrast, there is only one Type-II IFN, IFN-gamma [3], [2], [4].

IFN-alpha and IFN-beta bind to the type I IFN receptor ( IFN-alpha/beta receptor ) consisting of two subunits, Interferon (alpha, beta and omega) receptor 1 ( IFNAR1 ) and Interferon (alpha, beta and omega) receptor 2 ( IFNAR2 ) [5].

IFN-alpha/beta receptor lacks intrinsic kinase activity and thus relies on associated Janus kinases ( JAK1 and Tyk2 ) to phosphorylate receptor and signal transducing molecules, such as Signal transducers and activators of transcription 1 ( STAT1 and STAT2 ), after ligand-induced receptor clustering. IFNAR1 is pre-associated with Tyk2, and also binds STAT1 and STAT2. IFNAR2 is pre-associated with JAK1, STAT1 and STAT2 [4].

The tyrosine phosphorylation of STAT1 and STAT2 by JAK1 and Tyk2 leads to the formation of transcriptional complexes that translocate to the nucleus to induce expression of certain genes [2].

An important transcriptional complex that is induced by Type-I IFNs is the ISG Factor-3 complex ( ISGF3 ). The mature ISGF3 complex is composed of phosphorylated forms of STAT1 and STAT2 and Interferon regulatory factor 9 ( IRF9 ), which does not undergo tyrosine phosphorylation [2]. ISGF3 is the only complex that binds specific elements known as IFN-stimulated response elements (ISREs) that are present in the promoters of certain genes, such as Promyelocytic leukemia ( PML ), ISG15 ubiquitin-like modifier ( ISG15 ), Interferon-induced protein with tetratricopeptide repeats 2 ( ISG54 ) and Interferon alpha-inducible protein 6 ( IFI6 ) [6], [7], [8], [9].

In response to IFN-alpha, STAT1 and STAT2 can also form another transcriptional complex, STAT1/STAT2 heterodimer, that exhibits binding to the gamma-activated sequence (GAS) element of the Interferon regulatory factor 1 ( IRF1 ) gene [10], [11]. IRF1, in turn, can also induce the transcription of ISG15, ISG54 and IFI6 genes, whereas another IFN-alpha-inducible factor, Interferon regulatory factor 2 ( IRF2 ), is involved in the repression of gene transcription [12], [13], [14], [15].

Arginine methylation of STAT1 by Protein arginine methyltransferase 1 ( PRMT1 ) is an additional posttranslational modification that regulates transcription factor function required for proper IFN-alpha/beta-induced transcription [16].

A number of negative regulatory molecules limit the extent of type I IFN signaling. Suppressor of cytokine signaling 1 ( SOCS1 ) inhibits type I IFN signaling via interactions with IFNAR1, JAK1 and Tyk2 [17]. Protein tyrosine phosphatases non-receptor type 6 and 11 ( SHP-1 and SHP-2 ) dephosphorylate JAK1 and STAT1 and suppress their signaling [18], [19]. Protein tyrosine phosphatase non-receptor type 1 ( PTP-1B ) dephosphorylates Tyk2 and modulates signaling responses to IFN-alpha [20]. A type I IFN-inducible Ubiquitin specific peptidase 18 ( UBP43 ) binds directly to IFNAR2 and blocks the interaction between JAK1 and IFN-alpha/beta receptor [21].


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